Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL

Abstract

Central nervous system (CNS) relapse carries a poor prognosis in diffuse large B-cell lymphoma (DLBCL). Integrating biomarkers into the CNS-International Prognostic Index (CNS-IPI) risk model may improve identification of patients at high risk for developing secondary CNS disease. CNS relapse was analyzed in 1418 DLBCL patients treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy in the phase 3 GOYA study. Cell of origin (COO) was assessed using gene-expression profiling. BCL2 and MYC protein expression was analyzed by immunohistochemistry. The impact of CNS-IPI, COO, and BCL2/MYC dual-expression status on CNS relapse was assessed using a multivariate Cox regression model (data available in n = 1418, n = 933, and n = 688, respectively). High CNS-IPI score (hazard ratio [HR], 4.0; 95% confidence interval [CI], 1.3-12.3; P = .02) and activated B-cell‒like (ABC) (HR, 5.2; 95% CI, 2.1-12.9; P = .0004) or unclassified COO subtypes (HR, 4.2; 95% CI, 1.5-11.7; P = .006) were independently associated with CNS relapse. BCL2/MYC dual-expression status did not impact CNS relapse risk. Three risk subgroups were identified based on the presence of high CNS-IPI score and/or ABC/unclassified COO (CNS-IPI-C model): low risk (no risk factors, n = 450 [48.2%]), intermediate risk (1 factor, n = 408 [43.7%]), and high risk (both factors, n = 75 [8.0%]). Two-year CNS relapse rates were 0.5%, 4.4%, and 15.2% in the respective risk subgroups. Combining high CNS-IPI and ABC/unclassified COO improved CNS relapse prediction and identified a patient subgroup at high risk for developing CNS relapse. The study was registered at www.clinicaltrials.gov as #NCT01287741.

Conflict of interest statement

Conflict-of-interest disclosure: M.K. was employed by F. Hoffmann-La Roche Ltd. during the time of the analysis. L.H.S. has acted as a consultant for and received honoraria from Roche/Genentech, Amgen, Janssen, Celgene, AbbVie, and Seattle Genetics. I.B.-B. has served as a member of the advisory board for F. Hoffmann-La Roche Ltd. M.M. has acted as a consultant for F. Hoffmann-La Roche Ltd., Janssen, Sandoz, Takeda, Celgene, and Mundipharma; has served as a member of the speaker’s bureau for F. Hoffman-La Roche Ltd. and Takeda; and has served on the advisory board for F. Hoffmann-La Roche Ltd., Janssen, and Sandoz. D.S. has served on the advisory board for, and received research funding from, as part of a clinical trial, F. Hoffmann-La Roche Ltd. U.V. has received research funding from F. Hoffmann-La Roche Ltd.; has received honoraria from F. Hoffmann-La Roche Ltd., Takeda, and Gilead; and has served as a member of the advisory board for F. Hoffmann-La Roche Ltd., Celgene, and Janssen. F.Z. has acted as a consult or advisor for F. Hoffmann-La Roche Ltd., Janssen, Novartis, and Celgene; has served as a member of the speaker’s bureau for F. Hoffmann-La Roche Ltd., Celgene, Novartis, Gilead, and Takeda; and has received research funding from Celgene and Novartis. F.M., G.S., M.Z.O., G.R.F.-R., and T.N. are employees of F. Hoffmann-La Roche Ltd., and G.R.F.-R. owns stock in F. Hoffmann-La Roche Ltd. E.A.P., E.S.-G., and C.R.B. are employees of Genentech Inc. M.T. has received honoraria, research funding, travel, accommodations and/or expenses from, and has acted as a consultant or advisor to, F. Hoffmann-La Roche Ltd. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Risk for CNS relapse by CNS-IPI categories. (A) Overall GOYA study population (N = 1418); (B) population with COO data available (n = 933). EoT, end of treatment.

Figure 2.

Risk for CNS relapse by CNS-IPI and COO (CNS-IPI-C) in the COO available population (n = 933). H-R, high risk; I-R, intermediate risk; L-R, low risk; UNCL, unclassified.